Viruses belonging to the Herpesviridae family cause various infectious diseases in human and animals. For example, it is known that varicella zoster virus (VZV) causes varicella and shingles, and herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) cause herpes labialis, genital herpes and the like infections, respectively. In addition, infectious diseases caused by cytomegalovirus (CMV), EB virus (Epstein-Barr virus; EBV), human herpesviruses 6, 7 and 8 and the like herpesviruses have also been revealed in recent years.
Currently, acyclovir (ACV), its prodrugs varacyclovir (VCV) and fancyclovir (FCV) and the like nucleoside analogues are used as anti-herpesvirus drugs for VZV and HSV. These nucleoside analogues drugs are mono-phosphorylated into nucleoside monophosphate by viral thymidine kinase encoded by VZV and HSV and then converted into triphosphate compounds by cellular enzymes. Finally, the tri-phosphorylated nucleoside analogues are incorporated during the replication of viral genomic DNA by herpesvirus DNA polymerase and inhibit elongation reaction of viral DNA chains. Thus, since the reaction mechanism of existing anti-herpesvirus agents is based on the “competitive inhibition” for deoxynucleoside triphosphate, it is necessary to use these drugs in a high concentration in order to exert their antiviral effects. Actually, it is the present situation that these anti-herpes nucleoside analogues are administered in a high dosage of from several hundred mg to several g as their clinical dose. In addition, since nucleoside analogues are able to incorporate into host genomic DNA by DNA polymerase of the host, there is some apprehension about their mutagenicity.
On the other hand, some drugs which are non-nucleoside analogues and show anti-herpesvirus activity have recently been reported. For example, WO 97/24234 discloses amide or sulfonamide derivatives represented by the following formula (G) wherein an N atom is substituted with thiazolylphenylcarbamoylmethyl group or the like, which shows anti-HSV-1 activity and anti-CMV activity by inhibiting an HSV helicase-primase enzyme complex. However, the anti-VZV activity of these compounds is not illustratively disclosed. (In the formula, R is hydrogen, lower alkyl, amino, lower alkylamino or the like, R2 is hydrogen or lower alkyl, Q is not present or methylene, R3 is hydrogen, lower alkyl or the like, R4 is unsubstituted or substituted phenyl(lower) alkyl, 1-indanyl, 2-indanyl, (lower cycloalkyl)-(lower alkyl), (Het)-(lower alkyl) or the like, R5 is phenylsulfonyl, 1- or 2-naphthylsulfonyl, (Het)-sulfonyl, (unsubstituted or substituted phenyl)-Y—(CH2)nC(O), (Het)-(CH2)nC(O) or the like, Y is O or S, and n is 0, 1 or 2. See said document for details.)
WO 00/29399 also discloses amide or sulfonamide derivatives represented by the following formula (H) wherein an N atom is substituted with thiazolylphenylcarbamoylmethyl group, which shows anti-HSV-1 activity and anti-CMV activity, but the anti-VZV activity of these compounds is not illustratively disclosed. (In the formula, R1 is NH2, R2 is H, R3 is H, R4 is CH2Ph, CH2-(4-pyridyl), CH2-cyclohexyl or the like, and R5 is CO-(substituted phenyl), CO-(unsubstituted or substituted hetero ring) or the like. See said document for details.)
In addition, recently, there are reports on various herpesvirus protease inhibitors (Waxman Lloid et al., 2000, Antiviral Chemistry and Chemotherapy, 11, 1-22) and N-(carbonylphenyl)benzamide derivatives as HSV primase inhibitors (WO 00/58270). However, these documents do not disclose compounds having good anti-VZV activity, too.
Development of a non-nucleoside analogue anti-herpesvirus agent having sufficient anti-VZV activity and also having high safety is in great demand.